P740: IMPACT OF MAGROLIMAB IN COMBINATION WITH AZACITIDINE ON RED BLOOD CELLS IN PATIENTS WITH HIGHER-RISK MYELODYSPLASTIC SYNDROME (HR MDS)
Authors: J. Y. Chen, L. Johnson, K. M. McKenna, T. S. Choi, J. Duan, D. Feng, J. M. Tsai, N. Garcia-Martin, K. Sompalli, R. Maute, P. Vyas, R. Majeti, C. H. M. Takimoto, J. Liu, G. Ramsingh, M. P. Chao, J.-P. Volkmer, I. L. Weissman
Journal: HemaSphere (2022)

Background: Magrolimab is a monoclonal antibody that blocks CD47, a “don’t eat me” signal expressed on cancer cells, to escape immune surveillance and macrophage-mediated clearance. Prior preclinical studies have shown that CD47 is critical to red blood cell (RBC) homeostasis, with CD47 deficiency decreasing RBC half-life. Fc-mediated opsonization also depletes RBCs, raising concerns that potential on-target anemia could result from the use of anti-CD47 agents via multiple mechanisms. Nonetheless, several clinical trials have demonstrated that magrolimab can be safely administered as monotherapy, with an initial lower “priming” dose yielding transient anemia with compensatory reticulocytosis and no anemia observed at subsequent higher maintenance doses. However, the mechanism underlying this observed protection has not been fully defined. Aims: To describe manageable anemia in patients with HR MDS treated with magrolimab in combination with azacitidine (AZA) in a phase 1 clinical trial (NCT03248479) and further investigate the underlying mechanisms in preclinical models. Methods: In a multicenter prospective study, complete blood counts (CBCs), peripheral blood, and bone marrow (BM) were collected at prespecified time points from patients with HR MDS (n=57) treated with magrolimab in combination with AZA. CBCs were measured, and blood and BM samples were analyzed by flow cytometry for expression of CD47 on RBCs and white blood cells (WBCs). Magrolimab was initially administered as a priming dose (1 mg/kg) followed by an initial weekly maintenance dose (30 mg/kg) before transitioning to maintenance dosing every 2 weeks. AZA 75 mg/m2 was administered on days 1-7 of each 28-day cycle. Preclinical modeling studies were conducted with intact and Fc-deficient anti-mouse CD47 (MIAP410) and anti-human CD47 (magrolimab) antibodies in murine models, including C57BL/6J B-hSIRPA/hCD47 mice. Results: Combination treatment with magrolimab and AZA resulted in tolerable anemia that correlated with rapid, near-complete loss of CD47 in RBCs but not WBCs. The initial 1-mg/kg priming dose was sufficient for this CD47 loss, which persisted with subsequent 30-mg/kg maintenance doses. Both findings are consistent with prior clinical observations of magrolimab monotherapy in patients with solid tumors and magrolimab in combination with rituximab in patients with lymphoma. Our preclinical studies with mouse models revealed that CD47 removal is mechanistically independent of previously described RBC antigen modulation mechanisms and cellular compartments. Instead, this CD47 loss requires anti-CD47 cross-linking between RBCs and non-RBCs. Summary/Conclusion: Overall, these results support the idea that on-target magrolimab-mediated anemia is mitigated by a near-complete loss of RBC CD47. Patients with HR MDS treated with magrolimab in combination with AZA had tolerable anemia with the use of priming and maintenance doses.